Galphaq reduces cAMP production by decreasing Galphas protein abundance.
The heterotrimeric guanine nucleotide-binding protein Galphaq transduces signals from heptahelical transmembrane receptors (e.g., alpha(1)-adrenergic, endothelin 1A, and angiotensin II) to stimulate generation of inositol-1,4,5-trisphosphate and diacylglycerol. In addition, Galphaq decreases cAMP production, through unknown mechanisms, and thus affects physiological responsiveness of cardiac myocytes and other cells. Here, we provide evidence that Galphaq expression increases Galphas ubiquitination, decreases Galphas protein content, and impairs basal and beta(1)-adrenergic receptor-stimulated cAMP production. These biochemical and functional changes are associated with Akt activation. Expression of constitutively active Akt also decreases Galphas protein content and inhibits basal and beta(1)-adrenergic receptor-stimulated cAMP production. Akt knockdown inhibits Galphaq-induced reduction of Galphas protein. In addition, MDM2, an E3 ubiquitin ligase, binds Galphas and promotes its degradation. Therefore, increased expression of Galphaq decreases cAMP production through Akt-mediated Galphas protein ubiquitination and proteasomal degradation.
Tang
Tong
T
Department of Medicine , University of California San Diego, La Jolla, California 92039, USA; VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161, USA. Electronic address: ttang@vapop.ucsd.edu.
Gao
Mei Hua
MH
Department of Medicine , University of California San Diego, La Jolla, California 92039, USA; VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161, USA.
Miyanohara
Atsushi
A
The Vector Development Laboratory, University of California San Diego, La Jolla, California 92039, USA.
Hammond
H Kirk
HK
Department of Medicine , University of California San Diego, La Jolla, California 92039, USA; VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161, USA.
D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D054875:Ubiquitination
D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs